Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Systemic immunotherapies
Key points
-
The role of inflammation, including T cells, mast cells, prostaglandins, and cytokines, in the pathogenesis of androgenetic alopecia has been studied. Different approaches to address this inflammation have been recommended.
-
Use of anti-inflammatory immunotherapy in androgenetic alopecia is primarily through topical treatment; systemic immunotherapy is rarely prescribed.
-
When treated with systemic immunotherapy, patients who have both androgenetic alopecia and alopecia areata typically experience regrowth in a pattern that does not include regions affected by androgenetic alopecia.
-
Future directions may include topical and systemic targeted anti-inflammatory therapies.
Background, definitions, and history
Systemic immunotherapy is a class of medications characterized by their ability to affect the immune response. The specific mechanisms of drugs in this class can vary greatly depending on the immune cells that they target and the signaling molecules that they amplify or inhibit. It is notable that, historically, dermatopathologists have debated whether inflammation plays a role in androgenetic alopecia (AGA). The term “microinflammation” was penned to distinguish possible inflammatory pathways present in patients with AGA. , We now know that follicular microinflammation is driven by many factors, including perifollicular fibroblast activation, T-cell infiltration, prostaglandins, and mast cell degranulation ( Pearl 10.1 and Fig. 10.1 ). It is postulated that a combination of inflammatory, oxidative, and hormonal processes results in follicular miniaturization. , Scalp biopsies of male and female AGA frequently show chronic inflammation with the presence of lymphocytes and histiocytes, and a 2022 study located this perifollicular inflammation to be primarily at the isthmus and infundibulum of the hair follicle. T-cell infiltration, mast cell degranulation, and fibroblast activation have been postulated to lead to fibrosis of the perifollicular sheath and play a role in the abnormal hair cycle of AGA, which is characterized by a decreased anagen phase and normal or increased telogen phase. ,
PEARL 10.1:
The role of inflammation in androgenetic alopecia is unclear. The term “microinflammation” has been used to describe the possible inflammatory pathways present in AGA.
Indications and patient selection
Systemic immunotherapy refers to a broad class of therapeutics, and thus selection of such treatment varies widely based on each patient’s disease type, disease severity, and demographic factors. Of the nonscarring alopecias, treatment with systemic immunotherapy is more common in alopecia areata (AA) than in AGA or telogen effluvium (TE). In this chapter, we will discuss systemic immunotherapy as treatment for nonscarring alopecias and highlight the future directions of anti-inflammatory immunotherapy in AGA.
Androgenetic alopecia
Though systemic immunotherapies have not been widely indicated for use in AGA, their anti-inflammatory activity has led to some clinical research in this area. For example, prostaglandins have been found to contribute to the inflammation of AGA, and the production of prostaglandin D(2) (PGD2) is upregulated in biopsies taken from a bald male-pattern scalp compared with a hair-bearing scalp (level of evidence: 4). A clinical trial found that topical latanoprost, a prostaglandin F 2 analog, increases hair density in young men with mild AGA (level of evidence: 2b). , It has also been postulated that minoxidil may increase prostaglandin E 2 . However, another clinical trial assessing setipiprant, a PGD2 antagonist, found no significant difference with treatment versus placebo in men with AGA (level of evidence: 2b). Inflammatory genes, such as CASP7 and TNF, have also been shown to be overexpressed in male and female AGA tissue samples (level of evidence: 4).
Many existing treatment methods for AGA also have anti-inflammatory mechanisms ( Pearl 10.2 ). For example, treatment with the topical antihistamine cetirizine has been associated with clinical improvement in AGA, possibly related to the fact that mast cells produce PGD2, production of which is decreased with cetirizine (level of evidence: 2b). , Photobiomodulation is another expanding treatment modality for both male and female AGA and is postulated to work in part by reducing proinflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor-alpha (TNF- α), and interferon-gamma. , Jimenez et al. found that treatment with a low-level laser device increased terminal hair density in male and female pattern hair loss. As we understand more about the mechanism of platelet-rich plasma in the treatment of AGA, it appears that release of certain cytokines by platelets may also affect scalp inflammation. In the 2020s, dexpanthenol, an anti-inflammatory molecule that is a precursor to coenzyme A, has been shown to improve outcomes in AGA when administered systemically (level of evidence: 4). , The use of both systemic and topical anti-inflammatory immunotherapies may play a more prominent role in the future treatment of AGA, likely as a component of combination therapy plans.
PEARL 10.2:
Systemic immunotherapies are not widely indicated for the treatment of androgenetic alopecia. However, many existing treatment modalities, including antihistamines, photobiomodulation, and platelet-rich plasma, have anti-inflammatory effects.
Currently, the most commonly used systemic immunotherapies for the treatment of immune-mediated hair loss (e.g., AA) include oral steroids, janus kinase (JAK) inhibitors, and methotrexate ( Pearl 10.3 ). Corticosteroids are steroid hormones that increase anti-inflammatory signaling and decrease proinflammatory signaling. JAK inhibitors act on the JAK-STAT pathway to inhibit proinflammatory cytokines, such as IL-15, and suppress T-cell activation. Methotrexate is an antifolate agent with multiple anti-inflammatory mechanisms, including the inhibition of T-cell activation. Less commonly used systemic immunotherapies include cyclosporine and biologics. Cyclosporine works as an immunosuppressive agent by decreasing T-cell activity, mostly through inhibition of IL-2 transcription, and by binding to ubiquitous cyclophilin. Biologic drugs vary in their specific mechanisms.
PEARL 10.3:
Systemic immunotherapies are frequently used in the treatment of immune mediated hair loss, including alopecia areata and cicatricial alopecias. Such medications include oral steroids, janus kinase (JAK) inhibitors, methotrexate, cyclosporine, and biologics.
There are also outcomes associated with topical immunotherapies that are encouraging for systemic therapy. When randomized controlled trials for finasteride featured the use of coal tar shampoo in both control and placebo groups, questions arose whether the anti-inflammatory nature of coal tar shampoo could have confounded the results. Patients have long turned to alternative anti-inflammatory botanical agents for treatment of male pattern baldness, even in the absence of robust clinical data on their efficacy in most cases. Ginseng is a plant whose anti-inflammatory mechanisms have been studied in the setting of potential for hair growth (level of evidence: 5). Nigella sativa is a plant containing the anti-inflammatory compound thymoquinone and has been hypothesized to be a potential treatment for AGA; however, it has only been studied in TE (level of evidence: 5).
Other therapies discussed in this chapter, such as oral steroids, biologics, and cyclosporine, have not been demonstrated to have an effect on AGA. Methotrexate was found in one case to partially reverse a patient’s AGA after initiating the treatment for psoriasis.
Androgenetic alopecia and alopecia areata
Though systemic immunotherapy is commonly used in the treatment of cicatricial alopecias and certain nonscarring alopecias, such as AA, these therapies are not well studied in AGA. Treatment with systemic immunotherapy for AGA may be more relevant for patients with comorbid hair disease, such as in a patient with both AA and AGA. In these cases, treatment with systemic immunotherapy may need to be supplemented with targeted therapy for AGA.
Given the early positive response in AA patients to JAK inhibitor treatment, there was initial optimism that the treatment could be applied in other nonscarring alopecias. In a case series of four men with both AA and AGA, Yale et al. found that treatment with an oral JAK 1/2 inhibitor led to widespread scalp hair regrowth that spared the bitemporal regions (level of evidence: 4). Thus, this immunotherapy did not counteract the miniaturization of hair follicles observed in AGA. Additionally, clinical trials for topical immunotherapy in the form of a JAK inhibitor for AGA were discontinued when no clear efficacy was observed.
Expected outcomes
Androgenetic alopecia
Current literature suggests that positive outcomes are not anticipated with the systemic immunotherapies that have been studied to date in AGA, including systemic corticosteroids, JAK inhibitors, and cyclosporine. Outcomes have been better studied with topical immunotherapies for the management of AGA. Specifically, topical latanoprost and topical cetirizine have been associated with positive clinical outcomes. , Patients with concomitant AA and AGA may experience improvement of only their AA and not their AGA when treated with systemic immunotherapy ( Pearl 10.4 ). In one case, a patient with AGA experienced partial regrowth with methotrexate use for psoriasis (level of evidence: 4). However, we anticipate future clinical trials with systemic immunotherapy agents for use in AGA as our understanding of the inflammatory pathophysiology in AGA improves.
PEARL 10.4:
In patients with androgenetic alopecia, treatment with systemic immunotherapies may be indicated when there is comorbid immune-mediated hair loss (e.g., alopecia areata). However, in these patients, treatment with systemic immunotherapy may not lead to hair regrowth in areas affected by androgenetic alopecia.
Alopecia areata
In general, randomized clinical trials assessing the efficacy of treatment in AA are sparse, even for long-standing and gold-standard treatment methodologies such as intralesional steroid injections. Accordingly, there is no gold-standard metric against which to measure outcomes with new immunotherapy treatment methods.
Oral corticosteroids
Oral corticosteroids for the treatment of AA are relatively well studied compared to many of the other systemic immunotherapies discussed in this chapter. Factors associated with better outcomes from short-term or pulsed steroid treatment include decreased duration of disease and decreased disease surface area, and these patients may also experience disease relapse less frequently ( Pearl 10.5 ). Ophiasis pattern hair loss and alopecia universalis are associated with poorer outcomes with oral steroid treatment (level of evidence: 4). Studies on the effect of oral steroids for AA have a wide range of results, ranging from 0% to 100% efficacy, though these studies use varying metrics to assess for clinically significant regrowth (level of evidence: 5). Time to clinically significant response is generally around three months (level of evidence: 4). Response rates do not vary greatly for short-term treatment versus pulse treatment. Relapse rates are significant after discontinuation of oral steroid treatment, typically in at least half of patients discontinuing or tapering treatment (level of evidence: 4). ,
PEARL 10.5:
In the treatment of alopecia areata, oral corticosteroids may lead to better outcomes in patients with decreased duration of disease and decreased disease surface area. Relapse is common after discontinuation of oral steroids.
Oral janus kinase inhibitors
Results of the 2020 Alopecia Areata Consensus of Experts highlighted the increasing consensus regarding the efficacy of JAK inhibitors for AA ( Pearl 10.6 ). Experts agreed that this method is the ideal second-line treatment and can be used as monotherapy for AA (level of evidence: 1a). A 2019 meta-analysis of JAK inhibitors for AA found that 77.8% of patients responded to oral JAK inhibitors, which was greater than 22.2% of patients who responded to topical JAK inhibitor therapy (level of evidence: 1a). The study found no significant difference in response between disease categories, such as alopecia universalis versus patchy AA. Time to clinically significant regrowth has been noted to be roughly 3 months. Notably, relapse can be observed in AA patients discontinuing or tapering use of oral JAK inhibitors (level of evidence: 1b). , Clinical trials for JAK inhibitors in AA are underway, and one can anticipate further outcome data to emerge.
PEARL 10.6:
Janus kinase (JAK) inhibitors are efficacious second-line agents for the treatment of alopecia areata and may be used as monotherapy.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here
